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    Summary
    EudraCT Number:2020-004455-32
    Sponsor's Protocol Code Number:IMB101-006
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-02-24
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedDenmark - DHMA
    A.2EudraCT number2020-004455-32
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Exploratory Study on the Safety, Tolerability, and Pharmacodynamics of IMB-1018972 in Subjects with Angina due to Obstructive Coronary Artery Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A research study to determine the safety of IMB-1018972 and how it helps your heart use energy more efficiently to improve angina
    A.3.2Name or abbreviated title of the trial where available
    IMPROVE-Ischemia (IMB-1018972 to Improve Myocardial Response to Ischemia)
    A.4.1Sponsor's protocol code numberIMB101-006
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorImbria Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportImbria Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationImbria Pharmaceuticals, Inc
    B.5.2Functional name of contact pointKaren Jauregi
    B.5.3 Address:
    B.5.3.1Street Address265 Franklin Street, Suite #1702
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02110
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 617 675-4060
    B.5.5Fax number+1 617 675-4061
    B.5.6E-mailkj@imbria.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code IMB-1018972
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNinerafaxstat
    D.3.9.2Current sponsor codeIMB-1018972
    D.3.9.3Other descriptive nameIMB-1018972 trihydrochloride monohydrate
    D.3.9.4EV Substance CodeSUB206514
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Coronary artery disease (CAD)
    E.1.1.1Medical condition in easily understood language
    Coronary artery disease (CAD)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028601
    E.1.2Term Myocardial ischemia
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability of IMB-1018972 in subjects with obstructive CAD and inducible ischemia
    E.2.2Secondary objectives of the trial
    •To further assess the safety and tolerability of IMB 1018972 in patients with obstructive CAD and inducible ischemia
    •To assess the impact of IMB-1018972 on segmental (regional) MBF, measured with quantitative 15O-H2O PET
    •To assess the impact of IMB-1018972 on the severity and extent of myocardial ischemia, measured with quantitative 15O-H2O PET
    •To evaluate the impact of IMB-1018972 on the regional left ventricular contractile response to inotropic stress measured at DSE
    Only assessed for subjects with ∆WMSI > 1 at baseline in DSE (i.e. with evidence of inducible ischemia at baseline DSE study)
    •To measure the impact of IMB-1018972 on global myocardial deformation (strain) during inotropic stress, by AI-driven analysis of echo images acquired during DSE
    •To evaluate the impact of IMB-1018972 on global myocardial blood flow (MBF) during hyperemic stress
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Provide written informed consent before any screening procedures.
    2.Able and willing to comply with all study procedures and requirements.
    3.Male or female aged ≥35 years at screening
    4.History of stable angina (CCS grading I-III) or anginal equivalent
    within 12 months prior to screening
    5.Regular use of at least 1 anti-anginal medication for symptomatic
    treatment of angina (e.g. β-blocker or calcium channel blocker) for at
    least 2 weeks prior to start of dosing of study drug and likely to remain
    on this therapy as background anti-anginal treatment at envisaged
    stable doses for duration of study.
    6.Subjects on regular beta blockade must be able to safely abstain from
    beta blockers for 48 hours prior to DSE examinations in the opinion of
    the Investigator.
    7.LVEF≥ 45% by any imaging modality.
    8. History (e.g. within past 5 years) of obstructive CAD or stress-induced
    myocardial ischemia documented by any of the following:
    • CT or invasive angiography demonstrating ≥50% diameter stenosis in
    ≥1 major coronary artery OR in the setting of significant diffuse
    atheroma
    • Prior percutaneous coronary intervention (PCI)
    • Prior coronary artery bypass graft (CABG) surgery
    • PET myocardial perfusion imaging demonstrating MBF<2.4 mL/min/g
    in ≥2 ischemic contiguous segments or involving ≥10.0% of the
    myocardium(MBF must be <2.0 mL/min/g if it was obtained in the 3
    months prior to screening)
    • Stress echo or stress CMR demonstrating ≥2 ischemic contiguous
    segments
    • SPECT myocardial perfusion imaging demonstrating inducible
    perfusion defect in ≥2 ischemic contiguous segments
    9. Evaluable acoustic windows during contrast-enhanced, resting
    echocardiography
    10. Current 15O-H20 PET perfusion imaging demonstrating inducible
    ischemia defined as hyperemic MBF<2.0 mL/min/g in ≥2 ischemic
    contiguous segments and/or involving ≥10% of the myocardium.
    Patients with a hyperemic MBF of 2.0 to 2.4 mL/min/g
    may be eligible for randomization after discussion with the Sponsor
    E.4Principal exclusion criteria
    1.Clinically significant LMS or proximal LAD stenosis likely to warrant
    revascularization during the study period in the opinion of the
    investigator
    2.For those subjects planned for FDG-PET imaging, subjects with Type 2
    diabetes mellitus requiring regular insulin or diabetes that is suboptimally
    controlled (i.e. HbA1c > 8% or 64 mmol/l)
    3.Subjects with Type 1 insulin dependent diabetes mellitus (IDDM)
    4.Known allergy/intolerance/absolute contra-indication to trimetazidine
    (TMZ), adenosine, dobutamine or atropine (e.g. glaucoma),
    echocardiography contrast agent, or excipients of the IMP.
    5.If any of the following have occurred:
    •Any prior treatment with trimetazidine (TMZ)
    •In the 4 months prior to screening:
    i. NYHA functional class 3 or 4 HF
    ii. CABG
    •In the 2 months prior to screening:
    i. acute coronary syndrome
    ii. PCI
    iii. stroke/TIA
    •In the 1 month prior to screening, use of:
    i. perhexiline
    ii. meldonium
    6.Ongoing treatment with heparin or heparin derivatives
    7.SGLT2 and/or GLP-1 agonist therapy change (initiated or dose
    changed) within 2 months prior to Visit 1
    8.Presence of pacemaker, cardiac resynchronization therapy and/or
    implantable cardioverter defibrillator
    9. Severe valvular heart disease
    10.eGFR < 30 ml/min/1.73 m2 (calculated by CKD-EPI).
    11.ALT /AST and/or bilirubin > 2 x ULN at baseline
    12.History of Parkinson's disease, Parkinsonian symptoms, or clinically
    significant restless legs syndrome.
    13. Exacerbating reversible medical cause for angina (e.g. severe anemia,
    sustained hypertension defined as persistent BP > 160/90 mmHg,
    hyperthyroidism).
    14. Long QT duration at screening (QTcF duration >470 ms for males, and
    >480 ms for females), or previously diagnosed long QT syndrome, or
    first degree relative with diagnosed long QT syndrome.
    15. Permanent atrial fibrillation (AF).
    16. Left bundle branch block (LBBB)
    17. BMI ≤18, or body mass >180 kg that precludes imaging procedures.
    18. History of alcohol or drug abuse within the prior 2 years
    19. Female subjects who are of child-bearing potential or who are
    currently breast
    feeding
    20. Male subjects with female partners of child-bearing potential unable
    and unwilling to
    practice an approved method of birth control for the duration of the
    study and until 90
    days after the last dose of study drug (see section 6.3.1for approved
    methods)
    21. Any malignancy currently under active treatment (e.g. chemotherapy,
    radiation). Patients with a history or concurrent malignancy may be
    discussed on a case by case basis with the Sponsor. currently under
    active treatment (e.g. chemotherapy,
    radiation). Patients with a history or concurrent malignancy may be
    discussed on a case by case basis with the Sponsor
    22. Currently participating in or have participated in any other
    investigational drug or implantable medical device trial within 3 months
    prior to entry into this study.
    23. Any major surgical procedure planned during the study period
    24. Evidence of clinically significant renal, hepatic, hematological,
    gastrointestinal, pulmonary, metabolic-endocrine, neurological,
    urogenital or psychiatric disease that may constitute a health risk for the
    subject and/or would interfere with the evaluation of the results or any
    other reasons that, in the opinion of the investigator, make the subject
    unsuitable for enrollment. Specifically, site specific requirements for
    COVID must be followed
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of treatment emergent AEs (including AEs leading to study drug discontinuation and AEs leading to death)
    Incidence of treatment emergent SAEs
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety and tolerability will be assessed throughout the study
    E.5.2Secondary end point(s)
    1a.Changes in vital signs, physical examination, clinical laboratory findings and 12 lead electrocardiogram (ECG) findings.
    1b.Rate of death, nonfatal MI, and urgent revascularization
    1c.Number of hospitalizations for cardiac or noncardiac reasons
    1d.Frequency of cardiac ischemia-driven hospitalization and/or revascularisation while on study
    1e.Frequency of treatment interruptions or discontinuations
    2a.Change in hyperemic MBF in the segments that were ischemic at baseline
    2b.Change in resting segmental MBF from baseline to end-of-treatment in the segments that were ischemic at baseline
    2c.Change in MFR in ischemic segments detected at baseline
    3a.Change in number of ischemic segments during hyperemia (ischemia defined as absolute MBF ≤2.3 ml/kg/min)
    3b.Change in total ischemia burden measured as ischemia score summed across all segments, from baseline to end-of-treatment
    3c.Change in inducible perfusion defect, from baseline to end-of-treatment, expressed as % of myocardium
    4.Change in the maximal ∆WMSI from baseline to end-of-treatment
    5.Maximal change in each of the following left ventricular strain indices derived from DSE imaging measured from baseline to end-of-treatment:
    •Global longitudinal strain (GLS, %)
    •Global longitudinal strain rate (SR, sec-1)
    •Global longitudinal post-systolic strain index (PSI, %), i.e. post-systolic strain divided by peak strain
    6.Change in global hyperemic MBF (end-of-treatment – baseline), measured with quantitative 15O-H2O PET
    7.Change in absolute values of each of the following strain indices measured from baseline to end-of-treatment in myocardial areas with ischemia:
    •Regional longitudinal strain (GLS, %)
    •Regional longitudinal strain rate (SR, sec-1)
    •Regional longitudinal post-systolic strain index (PSI, %)
    8a.Change in the number of segments with inducible ischemia from baseline to end-of-treatment (i.e. the number of segments that increase in wall motion score by ≥1 grade)
    8b.Change in the mean WMSI between rest value and peak stress value
    8c.Change in total ischemic extent from baseline to end-of-treatment
    9a.Change in global myocardial 18F-FDG uptake & glucose utilization from baseline to end-of-treatment
    9b.Myocardial 18F-FDG uptake & glucose utilization in segments that were ischemic during baseline PET 15O-H2O PET scan
    E.5.2.1Timepoint(s) of evaluation of this end point
    a.Safety and tolerability will be assessed throughout the study
    b.Changes from baseline to end of treatment
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 33
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 65
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-09-21
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